Electrochemical Nickel-Catalyzed C(sp3)–C(sp3) Cross-Coupling of Alkyl Halides with Alkyl Tosylates

Formation of new C(sp3)–C(sp3) bonds is a powerful synthetic tool to increase molecular diversity, which is highly sought after in medicinal chemistry. Traditional generation of carbon nucleophiles and more modern cross-electrophile-coupling methods typically lack sufficient selectivity when cross-coupling of analogous C(sp3)-containing reactants is attempted. Herein, we present a nickel-catalyzed, electrochemically driven method for the coupling of alkyl bromides with alkyl tosylates. Selective cross-coupling transformations were achieved even between C(sp3)-secondary bromides and tosylates. Key to achieve high selectivity was the combination of the tosylates with sodium bromide as the supporting electrolyte, gradually generating small amounts of the more reactive bromide by substitution and ensuring that one of the reaction partners in the nickel-catalyzed electroreductive process is maintained in excess during a large part of the process. The method has been demonstrated for a wide range of substrates (>30 compounds) in moderate to good yields. Further expanding the scope of electroorganic synthesis to C(sp3)–C(sp3) cross-coupling reactions is anticipated to facilitate the switch to green organic synthesis and encourage future innovative electrochemical transformations.


Materials and Methods
1 H NMR spectra were recorded on a Bruker 300 MHz instrument. 13 C NMR spectra were recorded on the same instrument at 75 MHz. Chemical shifts (δ) are expressed in ppm downfield from TMS as internal standard. The letters s, d, t, q, and m are used to indicate singlet, doublet, triplet, quadruplet, and multiplet, respectively. Analytical HPLC analysis was carried out on a C18 reversed-phase (RP) analytical column (150 × 4.6 mm, particle size 5 mm) at 37 °C by using mobile phases A [water/acetonitrile 90:10 (v/v) + 0.1% TFA] and B (acetonitrile + 0.1% TFA) at a flow rate of 1.5 mL/min. The following gradient was applied: linear increase from solution 3% B to 100% B within 10 min. GC-mass spectrometry (MS) analysis was performed on a Shimadzu GCMS-QP2010 SE coupled with a DSQ II (EI, 70 eV). A fused silica capillary column Rtx-5MS column (5% diphenyl, 95% dimethylpolysiloxane, 30 m × 0.25 mm × 0.25 μm) was used. The injector temperature was set at 280 °C. After 1 min at 50 °C, the oven temperature was increased by 25 °C/min to 300 °C and maintained at 300 °C for 3 min. As a carrier gas, helium at 40 cm s - LA-ICP-MS system was tuned daily for maximum sensitivity analyzing the reference material NIST 612 "Trace Elements in Glass". The ICP-MS instrument was operated in standard (single quadrupole) mode and tuned to minimize the formation of oxides by monitoring the oxide ratio ( 232 Th 16 O + / 232 Th + , m/z 248/232 < 1%). Isotope ratios were monitored to confirm the absence of interfering polyatomic species. The laser beam spot size was adjusted to 50 µm and the frequency to 60 Hz generating a fluence of 3.5 J cm -2 . Helium was used as carrier gas with a flow rate of 0.55 L min -1 (0.30 L min -1 cell gas, 0.25 L min -1 ablation cup gas). Image construction was perform using the HDIP software v.1.6.6.d44415e5 (Teledyne). Electrode imaging and energy dispersive X-ray (EDX) analysis were performed using a Zeiss Gemini DSM 982 Field Emission Scanning Electron Microscope using built in secondary electron detectors for imaging and a RÖNTEC GmbH M-Series EDX-detector. In addition, element identification was performed using the Röntec-Tools software suite. All electrochemical reactions were carried out in IKA ElectraSyn 2.0 undivided cells (5 mL vials). Aluminum electrodes were cut to standard ElectraSyn 2.0 dimensions from an aluminum sheet (99%, Goodfellow). Electrodes were typically polished using sand paper (3000 grit) before use. All chemicals were purchased from standard vendors and used without further purification.

GC Analysis -Sample Preparation and Calibration
GC samples were prepared by diluting 100 μL aliquots from the crude solutions in 1 mL of ethyl acetate containing 0.1 M biphenyl. The diluted sample was filtered through a celite and sodium sulphate plug before being transferred to a GC sample vial. The vial was capped and the content of the vial was then directly analyzed by with the method described above in the Materials and Methods section. The calibration data for the components of the model reaction is shown in Figure S1.  Following the general conditions for the optimization of the reaction conditions described above, the electrochemical reaction was tested using DMA, NMP, MeCN and 1,4 dioxane as the solvent. After electrolysis, the crude reaction mixtures were analyzed by GC-FID (Table S2). Following the general conditions for the optimization of the reaction conditions described above, the electrochemical reaction was tested using several salts as the supporting electrolyte. After electrolysis, the crude reaction mixtures were analyzed by GC-FID (Table S3). Table S3. Optimization of the supporting electrolyte for the electrochemical coupling of 2-phenylethyl tosylate (1a) with bromo cyclohexane (1b) Optimization of the loading of the supporting electrolyte loading for the electrochemical coupling of

2-phenylethyl tosylate (1a) with bromo cyclohexane (1b)
Following the general conditions for the optimization of the reaction conditions described above with NiCl2·dme as the catalyst (10 mol%), the electrochemical reaction was tested using variable amounts of NaBr as the supporting electrolyte. After electrolysis, the crude reaction mixtures were analyzed by GC-FID ( Figure S2). Table S4. Optimization of the amount of supporting electrolyte for the electrochemical coupling of 2-phenylethyl tosylate (4a) with bromo cyclohexane (4b) Following the general conditions for the optimization of the reaction conditions described above, the electrochemical reaction was tested using several nickel sources as the catalyst. After electrolysis, the crude reaction mixtures were analyzed by GC-FID (Table S4).

Characterization of the cathode surface after the electrochemical reactions
The glassy carbon electrodes used in this work performed best when used for the first time. Interestingly, reused electrodes typically provided 10%-15% lower yield for the cross-coupling reaction. Reuse of the electrodes for additional experiments did no longer affect the reaction outcome, pointing to a stable modification of the carbon surface when the new electrode was used for the first time. To shed light into this material modification, the surface of a used electrode was analyzed by SEM-EDX and LA-ICP-MS ( Figure S3). SEM-EDX analysis pointed to coating of the carbon surface with either bromine or aluminum ( Figure S3, top). LA-ICP-MS revealed accumulation of bromine on the surface of the electrode that had been immersed in the reaction mixture during electrolysis ( Figure   S3, bottom). Monitoring of the tosylate/halide exchange rates in DMA for various alkyl tosylates.
A stock solution of DMA that contains NiBr2.dme catalyst (0.025 M), and NaBr supporting electrolyte (0.35 M) was prepared and purged with argon. The corresponding amounts of 1) 2-phenyl tosylate, 2) octyl tosylate, 3) 1-phenyl-2-propyl tosylate, 4) 4-terbutyl-1-phenyl tosylate were placed in a 4 ml glass vial followed by 3 ml of the DMA stock solution were added so that the concentration of the tosylate is 0.25 M. The vials were capped and the reaction mixture was stirred and purged with argon for 30 minutes. The reaction mixture was allowed to progress at room temperature while timely samples were collected and analyzed by GC-FID following the procedure above. In a separate experiment, the aluminum-containing precipitate from a model cross coupling reaction described in Table S1, entry 1 was filtered and added to the tosylate-bromide substitution experiment to investigate the effect of the aluminum salt on the kinetics. The amount of supporting electrolyte was reoptimized for the cross-coupling between octyl tosylate and cyclohexyl bromide. Thus, following the general conditions for the optimization of the reaction conditions described above with octyl tosylate as the substrate and NiCl2·dme as the catalyst (10 mol%), the electrochemical reaction was tested using variable amounts of NaBr as the supporting electrolyte. After electrolysis, the crude reaction mixtures were analyzed by GC-FID (Table S5).

Optimization of the amount of alkyl bromide for the electrochemical coupling of octyl tosylate (23a) with bromo cyclohexane (1b)
The amount of cyclohexyl bromide was reoptimized for the cross-coupling between octyl tosylate and cyclohexyl bromide. Thus, following the general conditions for the optimization of the reaction conditions described above with octyl tosylate as the substrate, the electrochemical reaction was tested using variable amounts of octyl bromide. After electrolysis, the crude reaction mixtures were analyzed by GC-FID (Table S6).

Synthesis of starting materials
Synthesis of alkyl tosylates. The synthesis of the alkyl tosylates employed as reactants was carried out using either tosyl chloride following method (1) or tosyl anhydride following method (2). Method Scheme S1. Alkyl tosylates prepared using Method A. Isolated yields are shown. S14 S14 Scheme S2. Alkyl tosylates prepared using Method B. Isolated yields are shown.

Electrochemical nickel-catalyzed cross-coupling of alkyl tosylates with alkyl bromides
A stock solution of DMA containing NiBr2.dme (0.025 M), 4,4'-di-t Bubpy (0.0375 M) and NaBr (0.1 M) was purged with argon for 30 min. The corresponding amounts of the alkyl tosylate and alkyl bromide were placed in a 5 ml IKA ElectraSyn 2.0 vial, followed by 3 mL of the aforementioned DMA stock solution. The cell cap was equipped with a glassy carbon cathode and an aluminum anode. The cell was capped and the reaction mixture was stirred and purged with argon for 30 minutes before the electrolysis was started. Then, the solution was electrolyzed under a constant current of 4 mA (2.7 mA/cm 2 ) under argon atmosphere while stirring it at 600 rpm. Electrolysis was continues until 3 F/mol of charge had been passed. After electrolysis, the crude reaction mixture was diluted with ethyl acetate and washed five times with an aqueous 20 wt% sodium citrate solution. The organic layer was dried over Na2SO4, the solvent evaporated, and the crude residue purified using column chromatography with petroleum ether/ethyl acetate as the eluent.

S21
Following the general procedure, the title compound was isolated as a colorless oil (107 mg, 65%).

Octylcyclohexane 35
Following the general procedure, the title compound was isolated as a colorless oil (75 mg, 51%).